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Post by Former NIMH Director Thomas Insel: Can We Prevent Psychosis?

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Each year, about 500,000 young people in this country seek help for symptoms that resemble the prodrome of a psychotic illness. They are not actively psychotic, but they may be struggling in school, dealing with odd thoughts, and becoming socially isolated. Some describe brief hallucinations or paranoid ideas. Many have become “basement kids,” playing video games alone most of the week and losing interest in the world above ground. Most of these youth will, ultimately, be fine. But about one in three of those identified as high risk will have a first psychotic episode within three years.1

Can we predict which teens will develop a psychotic illness? For heart attacks, we know that obesity, hypertension, and high blood lipids all increase risk. Predicting which adolescent with prodromal features will develop psychosis is not so easy. We lack biomarkers, like blood lipids, that increase risk. Indeed, in most studies, the majority of “high-risk” individuals never go on to develop a psychotic disorder. Very recently, the North American Prodrome Longitudinal Study (NAPLS) has improved prediction. Combining different types of information—cognitive testing, clinical features (e.g., unusual thoughts, suspiciousness, decline in social functioning), a history of traumatic events, and a family history of psychosis—over 70 percent of those identified as high risk went on to develop psychosis. For the first time we can accurately detect risk for psychosis in someone with prodromal symptoms, and the accuracy appears equal to or better than our predictions of heart disease or dementia.

The bad news is that we don’t yet have an intervention proven to prevent psychosis in those at risk. Several interventions have been tried, but most of the trials have had so few people converting to psychosis in either the treated or the control conditions, that efficacy was impossible to assess. A meta-analysis of preventive intervention studies described consistent benefit from cognitive therapy but rated the evidence as “modest” due to design limitations in the studies.2 A promising result with omega-3 fatty acids is currently being tested in a multi-site replication study. Antipsychotic or antidepressant medications do not appear useful for reducing conversion to psychosis in the few, small studies reported thus far.

A new report from the Early Detection and Intervention for the Prevention of Psychosis Multisite Effectiveness Trial, the largest early intervention study to date, claims that psychosis can be prevented.3 However, a number of editorials published online in recent weeks call this conclusion into question.4,5,6,7 In this study, subjects were divided into clinical low risk, clinical high risk, and early first episode psychosis groups. Only the latter two groups received the experimental intervention. Of the 205 high-risk cases, only 6.3 percent progressed to psychosis. But as the online editorials make clear, this study failed to demonstrate that the intervention prevented psychosis onset. The conversion rate was not statistically different from the clinical low-risk group (2.3 percent progressed to psychosis). While a conversion rate of 6.3 percent seems low, in the absence of a clinical high-risk group for comparison, it is unfortunately impossible to state how many psychotic events were averted or if the experimental intervention was useful for preventing psychosis.

Prevention studies targeting the psychosis prodrome raise a number of scientific and ethical issues that deserve consideration by the field. What is the best design for testing preventive interventions? What level of risk for future psychosis should be the threshold of participation for preventive trials? What are the consequences of labeling an adolescent as “high risk” for something as potentially stigmatizing as schizophrenia? Is the use of antipsychotic medication in adolescents who are not experiencing psychosis ever warranted, given the significant side-effects?

The most important question to be answered remains: what is the best way to prevent psychosis? Given the morbidity and mortality of psychotic illnesses, there can be little doubt that we need interventions to prevent its onset. Even delaying the onset of psychosis for five years could make a huge difference in outcomes. NIMH recently funded a series of prevention trials, targeting features of the clinical high risk period such as poor social functioning and neurocognitive deficits, and using a range of interventions from cognitive behavioral social skills training to cognitive training using online computer games. If low risk approaches to intervention are able to produce even a 10 percent reduction in incidence, there could be a profound public health impact. We are not there yet. But now that we have the tools available for predicting risk, we can get serious about preventing psychosis and enabling these young people to engage in, rather than withdraw from life.


1 Fusar-Poli P et al. The psychosis high-risk state: a comprehensive state-of-the-art review. 2013 Jan;70(1):107-20.

2 Stafford MR et al. Early interventions to prevent psychosis: systematic review and meta-analysis. BMJ. 2013 Jan 18;346:f185.

3 McFarlane WR et al. Clinical and Functional Outcomes After 2 Years in the Early Detection and Intervention for the Prevention of Psychosis Multisite Effectiveness Trial. Schizophr Bull. 2014 Jul 26. pii: sbu108. [Epub ahead of print]

4 Arango C, Kahn RS. More treatment for those most in need? A foregone conclusion? Schizophr Bull. 2014 Oct 25. pii: sbu149. [Epub ahead of print]

5 Carpenter WT, Buchanan RW. Early Intervention: How Early and With What? Schizophr Bull. 2014 Nov 14. pii: sbu160. [Epub ahead of print]

6 Heinssen RK, Insel TR. Preventing the Onset of Psychosis: Not Quite There Yet. Schizophr Bull. 2014 Nov 11. pii: sbu161. [Epub ahead of print]

7Kraemer HC. Methodological comments: McFarlane et al. Schizophr. Bull. 2014 Oct 16. pii: sbu139. [Epub ahead of print]